Project III: Summary/Abstract Abnormalities of balance and gait are common in Parkinson disease (PD), are largely unresponsive to dopamine replacement therapies, have no medical treatment options, and are major sources of morbidity. Our prior work, which will be further developed in Project II, indicates that degeneration of corticopetal basal forebrain (BF) and diffusely projecting brainstem peduculopontine (PPN) cholinergic neurons, in the context of deficient striatal dopaminergic function, contribute significantly to the progressive balance and gait deficits of PD (?3 Hit model?; detailed in Overview). This 3 Hit model proposes that a key mechanism of falls in PD is loss of cholinergic-mediated attentional compensation necessary to maintain gait in the hypodopaminergic state. ?4?2* nicotinic cholinergic receptors (nAChRs) are important mediators of CNS cholinergic neurotransmission subserving attention. Based on published human and animal data, and new preclinical data (Project I), our central hypothesis is that insufficient activation of ?4?2* nAChRs secondary to degeneration of cholinergic projections is a critical contributor to balance and gait deficits in PD. ?4?2* nAChRs are highly regulated ligand-gated ion channels and potential targets for pharmacotherapy to ameliorate balance and gait problems in PD. In this pilot target engagement study, we will study the subgroup of PD subjects with significant loss of cholinergic neurons, which will be identified by Project II and the Clinical Resource Core. We will evaluate key pharmacokinetic-pharmacodynamic features of ?4?2* nAChRs in the hypocholinergic, degenerating PD brains of these subjects using the ?4?2* nAChR partial agonist varenicline (VCN), PET imaging of ?4?2* nAChRs, and laboratory measures of gait function, postural control, and attentional function. We will use [18F]flubatine PET to determine the minimum VCN dose producing high ?4?2* nAChR occupancy in the hypocholinergic PD brain. Subacute VCN administration will be used to assess the effects of ?4?2* nAChR stimulation on gait function, postural control, and attentional function in hypocholinergic PD subjects. We predict that improved attentional function will correlate with improved gait function and postural control. These results will identify ?4?2* nAChRs as targets for future clinical trials in a well defined subgroup of PD patients, validate the novel animal model used in Project I, improve understanding of the mechanisms underlying gait and balance problems in PD, and implement new methods for evaluation of agents aimed at improving gait function and postural control deficits in PD. This work is directly responsive NINDS PD 2014 Research Report ?highest priority recommendations? calling for studies aimed at understanding mechanisms of and developing treatments for balance and gait disorders in PD (Clinical recommendations 2 & 3; Basic recommendation 3; Translational recommendation 6) and the Udall RFA request for pilot target engagement/pharmacodynamics studies.